Is FMO3 p.Ala458Val (c.1373C>T) pathogenic?

FMO3 p.Ala458Val (c.1373C>T) is classified Uncertain significance in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: likely pathogenic (0.6683); Very rare (popmax 0.00136%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FMO3 p.Ala458Val (c.1373C>T)?

FMO3 p.Ala458Val (c.1373C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FMO3 p.Ala458Val (c.1373C>T) in the general population?

FMO3 p.Ala458Val (c.1373C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about FMO3 p.Ala458Val (c.1373C>T)?

AlphaMissense predicts likely pathogenic (score 0.6683) — an in-silico prediction, not a clinical call.

FMO3 p.Ala458Val

c.1373C>T · rs773995199 · VCV2467373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6683 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6683	likely pathogenic
REVEL	0.422	indeterminate
SaProt	LLR -12.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.27 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,180,006 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,614,006 alleles · very rare exomes 17/1,461,820 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,750
African / African-American	0.00133%	74,924
South Asian	0.0011%	91,088

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FMO3
Protein: p.Ala458Val
Coding: c.1373C>T
MANE Select: NM_001002294
dbSNP: rs773995199
Type: single nucleotide variant
Location: chr1:171117216 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50

Full FMO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMO3 p.Tyr430His Uncertain significance ★★ same condition
FMO3 p.Thr532Ile Likely benign ★★ same condition
FMO3 p.Ala10Val Uncertain significance ★ ⚠ same condition
FMO3 p.Ala138Thr Uncertain significance ★ ⚠ same condition
FMO3 p.Ala367Val Uncertain significance ★ ⚠ same condition
FMO3 p.Ala378Val Uncertain significance ★ ⚠ same condition
FMO3 p.Arg500Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
FMO3 p.Asn268Ser Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fmo3-p-ala458val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown